Tissue engineering and cell therapy are a new and exciting approach to the treatment of acute and chronic diseases. The potential success of this therapeutic approach lies in the growing appreciation that most disease processes are not due to the lack of a single protein but develop due to alterations in complex interactions of a variety of cell products. Cell therapy is dependent on cell and tissue culture methodologies to expand specific cells to replace important differentiated processes deranged or lost in various disease states. Recent approaches have made progress by placing cells into hollow fiber bioreactors or encapsulating membranes as a means to deliver cell activities to a patient. The systemic inflammatory response syndrome, or SIRS, is a catastrophic sequela of a variety of clinical insults, including infection, pancreatitis, and cardiopulmonary bypass, and claims over forty thousand lives in the U.S. each year. The exceptionally high mortality associated with the syndrome is due in part to the development of the highly lethal multiple system organ failure syndrome (MOF) in a subset of patients with SIRS. The sequential failure of organ systems apparently unrelated to the site of the initial insult has been correlated with altered plasma cytokine levels observed in sepsis. The mortality is especially high in patients with MOF and acute renal failure. This proposal plans experiments to accomplish the following: 1) establish a 10-16 hour model of septic shock in the pig (Specific Aim 1) and 2) to assess the influence of a bioengineered cell based therapeutic device to reverse the progression of the septic disease process (Specific Aim 2) utilizing the 10- 16 hour porcine model. The data accrued in this Phase I program will allow for a proof of concept to justify planned experiments in Phase II to develop a miniature cellular device which will be accessed via an arterial/venous catheter system. At the end of Phase II, the developed pre-clinical data will be used for an IND application for the clinical testing of this therapeutic cellular device in treatment of septic shock. Relevance: The goal of this proposal is to develop a cell based therapy that can be used to reverse the serious clinical events associated with patients who develop septic shock. The success of this project would decrease the very high mortality rate of septic shock and therefore contribute to patient recovery from this devastating disease process. [unreadable] [unreadable]